WO2014052454A1 - Agents d'imagerie - Google Patents

Agents d'imagerie Download PDF

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WO2014052454A1
WO2014052454A1 PCT/US2013/061681 US2013061681W WO2014052454A1 WO 2014052454 A1 WO2014052454 A1 WO 2014052454A1 US 2013061681 W US2013061681 W US 2013061681W WO 2014052454 A1 WO2014052454 A1 WO 2014052454A1
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group
composition
hydrogen
labeled
independently selected
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PCT/US2013/061681
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English (en)
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David M. Raffel
Yong-Woon Jung
Keun-Sam JANG
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The Regents Of The University Of Michigan
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Priority to US14/428,876 priority Critical patent/US20150246142A1/en
Publication of WO2014052454A1 publication Critical patent/WO2014052454A1/fr
Priority to US15/367,856 priority patent/US20170190658A1/en
Priority to US15/891,819 priority patent/US10259781B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/06—Purification or separation of guanidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/06—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • Radionuclide imaging (e.g., nuclear medicine) is a key component of modern medical practice. This methodology involves the administration, typically by injection, of tracer amounts of a radioactive substance (e.g., radiotracer agents, radiotherapeutic agents, and radiopharmaceutical agents), which subsequently localize in the body in a manner dependent on the physiologic function of the organ or tissue system being studied.
  • a radioactive substance e.g., radiotracer agents, radiotherapeutic agents, and radiopharmaceutical agents
  • the radiotracer emissions most commonly gamma photons, are imaged with a detector outside the body, creating a map of the radiotracer distribution within the body. When interpreted by an appropriately trained physician, these images provide information of great value in the clinical diagnosis and treatment of disease.
  • Typical applications of this technology include detection of coronary artery disease (e.g., thallium scanning) and detection of cancerous involvement of bones (e.g., bone scanning).
  • gamma cameras The overwhelming bulk of clinical radionuclide imaging is performed using gamma emitting radiotracers and detectors known as "gamma cameras”.
  • diagnostic imaging such as magnetic resonance imaging (MRI), computerized tomography (CT), single photon emission computerized tomography (SPECT), and positron emission tomography (PET) have made a significant impact in cardiology, neurology, oncology, and radiology.
  • MRI magnetic resonance imaging
  • CT computerized tomography
  • SPECT single photon emission computerized tomography
  • PET positron emission tomography
  • Imaging agents are generally classified as either being diagnostic or therapeutic in their application.
  • diagnostic imaging agents have historically been a. mainstay in the nuclear pharmacy industry, during the past decade there has been increased interest in the development and use of radioactive imaging agents for radiotherapy. 'This shift in focus has been elicited primarily from research involving combining radioactive isotopes with
  • PET uses imaging agents labeled with positron-emitters such as 18 F, "C, 13 N, 15 0, 75 Br, 76 Br, and 124 B
  • SPECT uses imaging agents labeled with single-photon-emitters such as 201 T1, 99:n Tc, 123 I, and
  • glucose-based and amino acid-based compounds have been used as imaging agents.
  • Amino acid-based compounds are more useful in analyzing tumor cells due to their faster uptake and incorporation into protein synthesis.
  • n C- and 18 F-containing compounds have been used with success.
  • 11 C-containing radiolabeled amino acids suitable for imaging include, for example, L-[l" n C]leucine (Keen et al. J. Cereb. Blood Flow Metab. 1989 (9):429-45l herein incorporated by reference in its entirety), L-[l- ! ⁇ jtyrosine (Wiesel et al. J. Nucl. Med.
  • PET involves the detection of gamma rays in the form of annihilation photons from short-lived positron emitting radioactive isotopes including but not limited to 18 F with a half- life of approximately 110 minutes, ll C with a half- life of approximately 20 minutes, 1 N with a half-life of approximately 10 minutes, and. ;5 0 with a half-life of approximately 2 minutes, using the coincidence method.
  • SPECT uses longer-lived isotopes including but not limited to 99m Tc with a half- life of approximately 6 hours and 201 T1 with a half-life of approximately 74 hours.
  • the resolution in present SPECT systems is lower than that presently available in PET systems.
  • MIBG Radio-iodinated meta-iodobenzylguanidine
  • MIBG Radio-iodinated meta-iodobenzylguanidine
  • New compounds that find use as imaging agents within nuclear medicine applications have been described: for example, fluorine- 18-labeled phenethylguani dines. See, e.g., U.S. Pat. No.
  • a first step in particular embodiments of the technology uses a novel diaryliodonium salt precursor to introduce fluorine- 18 into the ring structure, followed by removal of a N-Boc protecting group to yield a radiolabeled 4-[ 18 Fjfluoro-meta-tyramine derivative in which the meta-hydroxy group remains protected by a benzyl group.
  • This intermediate is then converted from a primary amine to a. guanidine using N-N'- diBoc- 5-chlorobenzotriazole.
  • a further step deprotects the meta-hydroxy group to yield 4- [ i8 Fjfluoro-meta-hydroxy- phenethylguanidine (l 18 F]4F-MHPG; in some contexts, referred to by the name 4- [ 18 F]-MHPG).
  • the technology relates to new methods of producing radioactive compounds; in particular, the methods relate to using a diaryliodium salt precursor to introduce fluorine- 18 into the structure of a radiolabeled
  • the methods relate to preparing a i8 F-labeled primary amine intermediate followed by conversion to a guanidine.
  • the methods are used to produce an exemplary novel compound, [ 18 F]4F ⁇ MHPG.
  • the technology is contemplated to encompass related and generalized structures defining a unified set of novel diaryliodiu salt precursors that are used to prepare ls F-labeled phenethylguanidines as disclosed in, e.g., U.S. Pat. No. 7,534,418, which is incorporated by reference in its entirety for all purposes. Accordingly, provided herein is technology related in one aspect to compositions comprising an 18 F-labeled phenethylguamdine having a structure according to
  • R;, R-?, R3 ⁇ 4 R,j, and. R5 are independently selected from the group consisting of 18 F-labeled, 19 F, hydrogen, halogen, hydroxy!, guanyl, alkoxy, haloalkoxy, 18 F-labeled alkoxy, alky], haloalkyl, 18 F-labeled alky], amine, and an amine comprising one or more protecting groups (e.g., a protected amine);
  • Re and R7 are independently selected fro the group consisting of hydrogen, hydroxy!, alkoxy, haloalkoxy, 18 F -labeled alkoxy, halogen, amino, alkyl, haloalkyl, and 18 F-]aheled alkyl; and
  • Rs, Ra, Rio, and R11 are independently selected from the group consisting of hydrogen, carbamate, cyclic carbamate, amide, cyclic a mide, and a.
  • compositions comprising a 18 F- labeled phenethylguanidine, wherein the 18 F-labeled phenethylguanidine is produced by a method comprising radiofluorinating an iodonium salt with an [ 18 F] fluoride ion source, e.g., as described by Reaction l: Reaction Formu
  • the iodonium. salt has a structure according to
  • R; , !3 ⁇ 4, Rs, R-i, and R5 are independently selected from the group consisting of R 1 2-L hydrogen, halogen, hydroxyl, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or more protecting groups (e.g., a protected amine); Re and. R?
  • R12 is a phenyl ring or a heterocyclic ring comprising hydrogen, hydroxyl, alkyl, halogen, alkoxy, carbonyi, cyano, and'or a nitro group.
  • the [ 18 F] fluoride ion source is a no-carrier-added
  • the no-carrier- added [ 1S F] fluoride ion source is selected from the group consisting of potassium fluoride / Kryptofix[2,2,2], cesium fluoride, tetraalkylammonium fluoride, and a solid phase fluoride.
  • X ⁇ is a counter ion. selected from the group consisting of halide, sulfate, formate, bromate, tosylate, trifluoracetate, triflate, mesylate, hexaflate, acetate, ascorbate, benzoate, and phosphate.
  • compositions are also provided that furthermore comprise a free radical scavenger, e.g., as a component of a reaction in which the compositions and compounds according to the technology are made.
  • free radical scavengers include, in some embodiments, 2,2,6,6-tetra.methylpiperidine-N- oxide, 4-aminobenzoic acid, 1,1-diphenylethylene, galvinoxyl, gentisic acid, hydroquinone, thiophenol, DL-alpha-tocopherol, and 2,6-di-tert-butyl-4- methylphenol (BHT).
  • the compositions provided further comprise water.
  • a reaction is heated., e.g., in some
  • compositions are produced according to a method that comprises heating or microwave irradiation of a reaction vessel holding the iodonium salt and the [ 18 Fj fluoride ion source.
  • compositions comprising an 18 F-labeled phenethylguanidine, wherein the 18 F-labeled phenethylguanidine is produced by a method comprising radioiluorinating an iodonium salt of
  • Step 2 coupling with guanidinating reagent
  • the iodonium salt of phenethylamine is
  • Ri', ]3 ⁇ 4', R3', R4', and R5' are independently selected from, the group consisting of Rio'— I, hydrogen, halogen, hydroxy!, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or more protecting groups (e.g., a protected amine);
  • Re' and R7' are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, haloalkoxy, halogen, amino, alkyl, and haloalkyl;
  • Rg' and R9' are independently selected the group from consisting of hydrogen, carbamate, cyclic carbamate, amide, cyclic amide, and nitrogen-protecting group.
  • the technology is not limited in the guanidinating agent that can be used; for example, in some embodiments, the guanidinating reagent is selected from the group consisting of a cyamide, cyanobromide/ammonia, an S ⁇
  • alkylisothiouronium salt a carboi.rn.ide, a chloroformamidine, a
  • dichloroisocyanide an aminoimnomethanesulfonic acid, Omethylisourea hydrogen sulfate, lH-pyrazole- l-carboxamidine hydrochloride, benzotriazole-1- carboxamidiniiim tosylate, IH-pyrazole ⁇ 1 ⁇ [N,N'-Bis(tert- butoxy benzyloxycarbonyl)]-carboxamidine, N,N'-bis(tert- butoxy/benzyloxycarbonyl)-N"-trifly guanidine, N,N'-bis(tert- butoxy/benzyloxycarbony])-2-methyl-2-thiopseudourea, N,N'-bis(tert- butoxy benzyloxycarbonyl)-thiourea, N.N'-bisitert-butoxy benzyloxycarbonyl)- carboimide, and N,N'-bis(tert-butoxy/benzyloxycarbon
  • Rio' is a phenyl ring or a heterocyclic ring comprising a hydrogen, hydroxyl, alkyl, halogen, alkoxy, carbonyl, cyano, and/or a nitro group.
  • Rio' comprises a solid support linker, e.g., Linker of So!id Support—
  • Certain embodiments comprise a composition produced using an iodonium salt of phenethylarnine that is an [ 18 F] -labeled phenethylarnine derivative according to a structure
  • th 18 Fj -labeled phenethylguanidine has the structure
  • the [ 18 F] fluoride ion source is a no-carrier-added [ 18 F] fluoride ion source, e.g., a potassium fluoride / Kryptofix [2,2,2] , cesium, fluoride, and/or tetraalkylammonium fluoride.
  • X " is a counter ion selected from the group consisting of halide, sulfate, formate, borate, tosylate, trifluoroacetate, triflate, mesylate, hexaflate, acetate, ascorbate, benzoate, and phosphate.
  • the compositions comprise a free radical scavenger, e.g., as a component of a reaction to produce embodiments of the technology comprising compositions and compounds.
  • exemplary free radical scavengers include 2,2,6,6-tetramethylpiperidine-N-oxide, 4-aminobenzoic acid, 1, 1 'diphenylethylene, galvinoxyl, gentisic acid, hydroquinone, thiophenol, DL- alpha-tocopherol, and 2,6-drtert-butyl-4-methylphenol (BHT).
  • the compositions comprise water.
  • compositions according to the technology are produced by a method that comprises heating or microwave irradiation of a reaction vessel holding the iodonium salt and the [ 18 F] fluoride ion source.
  • embodiments of the technology comprise compositions wherein the iodonium salt is produced by a method comprising reacting a first compound having the structure
  • Ri , R2, R3, R4, and R5 are independently selected from the group consisting of XaSn, hydrogen, halogen, hydroxy!, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or more protecting groups (e.g., a protected amine); e and R?
  • R12 is a phenyl ring or a heterocyclic ring comprising a hydrogen, hydroxy!, alkyl, halogen, alkoxy, carbonyl, cyano, and/or a nitro group.
  • compositions e.g., a reaction pathway intermediate
  • a method comprising reacting a compound having the structure
  • Ri, 3 ⁇ 4, R3, R 4 , and R5 are independently selected from the group consisting of halogen (e.g., iodo, bromo), hydrogen, hydroxyl, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or more protecting groups (e.g., a protected amine); Re and R? are halogen (e.g., iodo, bromo), hydrogen, hydroxyl, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or more protecting groups (e.g., a protected amine); Re and R? are examples of halogen (e.g., iodo, bromo), hydrogen, hydroxyl, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or
  • R9, Rio, and Rn are independently selected the group consisting of hydrogen, carbamate, cyclic carbamate, amide, cyclic amide, and nitrogen- rotecting group; and.
  • X is an alkyl group.
  • the iodonium salt of phenethylamine is produced by a method comprising reacting a first compound having the structure
  • Ri', R2', R3', R4', and R5' are independently selected from the group consisting of X3S11, hydrogen, halogen, hydroxy!, guanyl, alkoxy, haloalkoxy, alkyl, haloalkyl, amine, and an amine comprising one or more protecting groups (e.g., a protected amine);
  • Re' " and K7' are independently selected from the group consisting of hydrogen, hvdroxyl, alkoxy, haloalkoxy, halogen, amino, alkyl, and haloalkyl;
  • Rs' and R9' are independently selected, the group from hydrogen, carbamate, cyclic carbamate, amide, cyclic amide, and nitrogen-protecting group; and X is an alkyl group.
  • Rio' is a phenyl ring or a heterocyclic ring comprising hydrogen, hydroxyl, alkyl, hal
  • compositions wherein a compound is produced by a method comprising reacting a compound having the structure
  • Ri', R2', R3', E ', and R5' are independently selected from the group consisting of iodo, bromo, hydrogen, halogen, hydroxyl, guanyl, alkoxy, haloalkoxy, u lkyl.
  • haloalkyl, amine, and an amine comprising one or more protecting groups e.g., a protected amine
  • Re' and R?' are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, haloalkoxy, halogen, amino, alkyl, and haloalkyl
  • Rs' and g' are independently selected from the group consisting of hydrogen, carbamate, cyclic carbamate, amide, cyclic amide, and nitrogen-protecting group.
  • the compounds and compositions provided by the technology find use in imaging a tissue, cell, organ, e.g., in a subject. Accordingly, the technology relates, in some embodiments, to methods of imaging comprising contacting a tissue to be imaged with an 18 F ⁇ labeled phenethylguanidine, or salt or derivativ thereof, and imaging the tissue.
  • the tissue is selected from the group consisting of heart and adrenal medulla.
  • the imaging is positron emission tomography (PET).
  • the technology relates to embodiments of methods for manufacturing an 18 F-labeled phenethylguanidine having a structure according to
  • the technology relates to embodiments of methods for manufacturing an [ 18 F] -labeled
  • the technology provides an 18 F ⁇ labeled phenethylguanidine, or salt, free base, or derivative thereof, for use as an imaging agent.
  • the labeling technology is not limited to labeled phenethylguanidines.
  • the technology is applicable to produce i8 F-labeled arylalkylguani dines, 18 F-labeled ar3d-Y-alkylgua.nidin.es, and/or 18 F- labeled heteroarylalkylguanidin.es.
  • the technology relates to embodiments of arylalkylguanidme compounds having a general structure ⁇
  • n 0, 1 , 2 or 3
  • L, M, N or Q CH 2 , CH, O, N, NH, S, CO, alkyl, haloalkyl, alkoxy, haloalkoxy,
  • arylalkylguanidines i8 F-labeled aryl-Y- alkylgua.nidin.es
  • 18 F-labeled heteroarylalkylgua.nidin.es e.g., for use as imaging agents, e.g., in PET imaging.
  • some embodiments provide methods in which an ls F-labeled arylalkylguanidme is produced from an iodonium salt precursor by a single step reaction in solution, e.g., lodonium Salt
  • the technology provides related embodiments in which an arylalkylguanidiiie is produced from an iodonium salt precursor in a single step using a linker, e.g.,
  • Step 2 coupling with guanidinating reagent
  • some embodiments provide methods in which an 18 F ⁇ labeled aryl-Y-alkylguariidine is produced from an iodonium. salt precursor by a single step reaction in solution, e.g.,
  • the technology provides related embodiments in which an aryhY-alkylguanidine is produced from an iodonium salt precursor in a single step using a linker, e.g., Linker of Solid
  • Step 2 coupling with guanidinating reagent
  • some embodiments provide methods in which an 18 F -labeled heteroarylalkylguanidine is produced from an iodonium salt precursor by a single step reaction in solution, e.g.,
  • heteroarylalkylguamdine is produced from an iodonium salt precursor in a single step using a linker, e.g.,
  • Step 2 coupling with guanidinating reagent
  • Figure 1 shows a reaction scheme depicting a radiosynthetic method for preparing 18 F ⁇ labeled phenethylguanidines using diaryliodium salt precursors containing a phenethylguanidine moiety.
  • Figure 2 shows reaction schemes depicting radiosynthetic methods for preparing 4-[ i8 Fjfluoro-iz?e ⁇ a-hydroxyphenethylguanidine using a diaryliodium salt precursor containing a. protected phenethylamine moiety.
  • This method can be generalized to prepare many other 18 F-pheiiethylguanidiiie structures, such as those described in U.S. Pat. No. 7,534,418.
  • Figure 2A and Figure 2B show two exemplary reaction schemes related to the technology provided herein, e.g., Figure 2 shows an embodiment for the automated radio synthesis of 4-[ 18 F]fluoro- nefer hydroxyphenethylguanidine ([ 18 F]4F-MHPG, compound 1).
  • Figure 3 is a plot showing the kinetics of [ U C]4F-MHPG and [ 18 F]4F- MHPG in isolated rat hearts.
  • Figure 4 is a plot showing reverse-phase HPLC analysis of [ 18 F]4F-MHPG and its metabolites in rhesus macaque plasma.
  • Figure 4A shows a representative HPLC trace for a. blood sample drawn at t - 2 min after tracer injection.
  • Figure 4B shows that 100% of the compound was in the sulfur-conjugated form after in vitro incubation of the parent compound with a monkey liver cytosol fraction and 3'-pho8pho-adenosine-5'phosphosulfate (PAPS).
  • Figure 5C shows the structure of the sulfur conjugated form.
  • Figure 5 is a plot showing metabolic breakdown of [ 18 F]4F-MHPG in the plasma of a rhesus macaque monkey.
  • Figure 6 is a plot showing kinetics of [ 18 F]4F-MHPG in whole blood (lower trace) and left ventricle (top trace) in a rhesus macaque monkey.
  • Figure 7 is a diagram showing a compartmental model used to analyze the myocardial kinetics of [ 18 F]4F-MHPG.
  • Figure 8 is a series of plots showing compartmental modeling of [ 18 F]4F- MHPG kinetics in monkeys for control (left), moderate desipramine (DMI) dose blockade of cardiac NET (middle), and. high DMI dose (right).
  • DMI moderate desipramine
  • Figure 9 is a plot showing dose-response curves of net uptake constants & (ml/ ' miii/g) derived from either kinetic compartmental modeling (circles) or Patlak graphical analysis (triangles) of [ !8 Fj4F-MHPG kinetics in rhesus macaque monkeys.
  • Figure 10 is a plot showing Patlak analysis of the myocardial kinetics of [ 18 F]4F-MHPG kinetics in rhesus macaque monkey.
  • Figure 11 is a plot showing Patlak analysis of the myocardial kinetics of j. 18 F]4F"MHPG in rhesus macaque monkey.
  • Figure 12 is a plot showing rapid neuronal uptake of n 01abeled phenoxyethylguanidines in an isolated rat heart model.
  • Figure 13 is a plot showing the rapid neuronal uptake and long neuronal retention times of ri C-labeled fluorcrphenoxyethylguanidines in the isolated rat heart model.
  • Figure 14 is a plot showing the kinetics of " Oguanoxan (GOX) and two ring-hydroxylated analogs, 11 C"7-hydroxy-guanoxan (7H-GOX) and n C-6- hydroxy-guanoxan (6H-GOX) .
  • the methods employ a 18 F-labeling step followed by one or two simple steps to yield the final radiolabeled product. It is contemplated that these methods permit automation of the process and thus allow for the routine commercial preparation of the target radiophamaceuticals at central distribution facilities.
  • the radiosynthetic methods provided here (see, e.g.. Figures 1 & 2) utilize a diaryliodonium salt precursor as a means of incorporating fluorine- 18 into the phenyl ring of a phenethylguanidine structure. Embodiments of the methods differ in the specific structures of the side chains of the precursors and of the 18 F-labeled intermediate compounds that are ultimately converted into the target 18 F-phenethylguanidine.
  • in vitro refers to an artificial environment and to processes or reactions that occur within an artificial environment.
  • in vitro environments may include, but are not limited to, test tubes and cell cultures.
  • in vivo refers to the natural environment (e.g., an animal or a cell) and to processes or reactions that occur within a natural environment.
  • the terms “subject” and “patient” refer to any animal, such as a mammal like a dog, cat, bird, livestock, and preferably a human (e.g., a human with a disease such as obesity, diabetes, or insulin resistance).
  • an effective amount refers to the a mount of a composition sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.
  • administration refers to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject.
  • exemplary routes of administration to the human body can be through the eyes
  • ophthalmic mouth (oral), skin (transdermal, topical), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.), and the like.
  • co -administration refers to the administration of at least two agents or therapies to a subject. In some embodiments, the co ⁇ administration of two or more agents or therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second
  • agent/therapy Those of skill in the art understand that the formulations and/or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co ⁇ administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent.
  • a potentially harmful agent e.g., toxic
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use,
  • compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.
  • sample is used in its broadest sense. In one sense, it is meant to include a specimen or culture obtained from any source, as well as biological and environmental samples. Biological samples may be obtained from animals (including humans) and. encompass fluids, solids, tissues, and gases. Biological samples include blood products, such as plasma, serum and the like. Environmental samples include environmental material such as surface matter, soil, water, crystals and industrial samples. Such examples are not however to be construed as limiting the sample types applicable to the present technology.
  • alkyi and the prefix “alk.-” are inclusive of both straight chain and branched chain saturated or unsaturated groups, and of cyclic- groups, e.g., cycloalkyl and cycloalkenyl groups.
  • acyclic alkyl groups are from 1 to 6 carbons.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 8 ring carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyelopentyl, cyclohexyl, and adamantyl groups, Alkyl groups may be substituted with one or more substituents or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, alkylsilyl, hydroxy!, fluoroalkyl, perfluoralkyl, amino, amiiioalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • alk the number of carbons contained in the alkyl chain is given by the range that directly precedes this term, with the number of carbons contained in the remainder of the group that includes this prefix defined elsewhere herein.
  • C1-C4 alkaryl exemplifies an aryl group of from 6 to 18 carbons (e.g., see below) attached to an alkyl group of from 1 to 4 carbons.
  • aryl refers to a carbocyclic aromatic ring or ring system. Unless otherwise specified, aryl groups are from 6 to 18 carbons.
  • aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl groups.
  • heteroaryl refers to an aromatic ring or ring system that contains at least one ring heteroatom (e.g., O, S, Se, N. or P). Unless otherwise specified., heteroaryl groups are from. 1 to 9 carbons.
  • Heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolvi, triazolyl, tetrazolyl, oxacliazolyl, oxatriazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazyl, benzofiiranyl, isobenzofiiranyl,
  • heterocycle refers to a non-aromatic ring or ring system, that contains at least one ring heteroato (e.g., O, S, Se, N, or P). Unless otherwise specified, heterocyclic groups are from 2 to 9 carbons.
  • Heterocyclic groups include, for example, dihydropyrrolyl, tetrahydropyrrolyl, piperaziny], pyranyl, dihydropyranyl, tetrahydropyranyl, dihydrofiiranyl, tetrahydrofuranyl, dihydrothiophene, tetrahydrothiophene, and morpholinyl groups.
  • Aryl, heteroaryl, or heterocyclic groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of Ci— 8 alkyl, hydroxy, halo, nitro, Ci-e alkoxy, Ci- ⁇ alkylthio, trifiuoromethyl, Ci-e acyl, arylcarbonyl, heteroarylcarbonyl, nitrile, Ci-e alkoxycarbonyl, alkaryl (where the alkyl group has from 1 to 4 carbon atoms), and alkheteroaryl (where the alkyl group has from 1 to 4 carbon atoms).
  • alkoxy refers to a chemical substituent of the formula OR, where B. is an alkyl group.
  • aryloxy is meant a chemical substituent of the formula OR', where R' is an aryl group.
  • C x - y alkaryl refers to a chemical substituent of formula RR', where R. is an alkyl group of x to y carbons and. R' is an aryl group as defined elsewhere herein.
  • C x - y alkheteraryl refers to a chemical substituent of formula RR", where R is an alkyl group of x to y carbons and R" is a heteroaryl group as defined elsewhere herein.
  • haJide or "halogen” or “halo” refers to bromine, chlorine, iodine, or fluorine.
  • non-vicinal O, S, or N refers to an oxygen, sulfur, or nitrogen heteroatom substituent in a linkage, where the heteroatom substituent does not form a bond to a saturated carbon that is bonded to another heteroatom.
  • R n --I or "R---I” represents a group wherein the iodine atom ("I") is bonded to the main structure, unless specified otherwise.
  • X3S11 represents a group wherein the tin atom ("Sn”) is bonded to the main structure, unless specified otherwise.
  • Koser's reagent refers to hydroxy(tosyloxy)iodobenzene (" ⁇ "; PM(OTs)OH)), e.g., as described in Koser, et al. (1982) J. Org Chem. 47: 2487.
  • the present technology provides novel compounds and. novel methods for producing compounds that find use as imaging agents within nuclear medicine applications (e.g., PET imaging and SPECT imaging).
  • the present technology also provides methods for producing imaging compositions for use within nuclear medicine applications. Exemplary compounds and methods of the present technology are described in more detail in the following sections.
  • Nuclear Radiology is a sub- specialty of Radiology in which radiotracing agents (e.g., compounds containing radioactive forms of atoms) are introduced into the body for the purpose of imaging, evaluating organ function, or localizing disease or tumors.
  • Radiolabelled. compounds are used, for example, for both tumor detection and tumor therapy.
  • Many tumor cells have a higher density of cell receptors for various circulating compounds than do non-tumor cells; e.g., endocrine tumors show a. high density of cell surface receptors for somatostatin and brain gliomas show a high density of receptors for epidermal growth factor.
  • aiigiogenesis the formation of new blood vessels from established microvasculature, is a critical process for tumor growth. Primary tumors and metastases will not grow beyond 2 mm in diameter without an enhanced vascular supply. Angiogenic cells also have a higher density of cell receptors for various circulating compounds than do noir angiogenic vascular tissue; e.g., receptors for both somatostatin and vascular endothelial growth factor are higher in angiogenic tissue. Thus, a tumor can also be detected by radiolabeled compounds binding to the angiogenic cells that are closely associated with the tumor cells.
  • the present technology provides new 7 compounds and new 7 methods of producing compounds useful as radiotracing agents.
  • the compounds are structurally related to iijei,3-iodobenzylguanidine (MIBG) and possess kinetic properties superior to MIBG for nuclear medicine applications.
  • the radiotracing agents of the present technology provide a slower cellular uptake rate and a longer cellular retention length.
  • the present technology provides radiolabeled
  • radio-halogens such as iodine- 123 (i23j) f or single photon imaging (e.g., SPECT imaging), iodine- 131 ( 131 I) for radiotherapy of adrenergic tumors, and carbon- 11 ( 11 C) or fluorine- 18 ( 18 F) for positron emission tomography imaging (e.g., PET imaging).
  • radio-halogens such as iodine- 123 (i23j) f or single photon imaging (e.g., SPECT imaging), iodine- 131 ( 131 I) for radiotherapy of adrenergic tumors, and carbon- 11 ( 11 C) or fluorine- 18 ( 18 F) for positron emission tomography imaging (e.g., PET imaging).
  • positron emission tomography imaging e.g., PET imaging
  • Phenethylguanidines differ from benzylguanidines in that they have an additional carbon atom in the side chain of the molecule.
  • the two-carbon side chain structure of phenethylguanidines is similar to that of norepinephrine (NE), the endogenous neurotransmitter of sympathetic neurons in the heart:
  • Additional exemplary compounds related to the technology include, but are not limited to, (--)-beta-hydroxyphenethylguanidine, ⁇ 1'a-methoxy- pheneth3dguanidme, mei ⁇ 3 ⁇ 4-hydroxyphenethylguanidine, panv
  • the compounds of the present technology are radio-labeled (e.g., n C, 1 C, 18 F, i31 I and 123 I).
  • the compounds of the present technology are described by the following chemical formula :
  • Ri, I3 ⁇ 4, R.3, R 4 and Rs are the same or different and are independently selected from, the group consisting of H, halogen, hydroxyl, guanyl, methoxy, methyl, amino, and nitro, wherein Re is selected from the group consisting of H and hydroxyl, and wherein R? is H or CHs.
  • the compound is selected from the group consisting of [ n C](-)-beta- hydroxyphenethylguanidine, [ 11 C] .?a J r,3-methoxy-phenethyIguanidine, [ n C ⁇ meta ⁇ hydroxyphenethylguanidine, l rs -C] 3 ⁇ 43r, hydroxyphenethylguanidine, [ !
  • the halogen is selected from the group consisting of 18 F, m At, - -'Br. , and 123 L
  • Additional exemplary embodiments include, but are not limited to, methods of producing compounds such as the following:
  • the invention includes methods and compounds related to arylalkylguaiiidines, aryl-Y-alkylguanidines, and
  • heteroarylalkylguanidines Arylalkylguanidin.es are generally described by the following formu r Alkoxy
  • 18 F is added to an arylalkylguanidine compound.
  • One compound resulting from such fluorinations is as follows :
  • n 1 , 2, or 3
  • 18 F is added to an aryl-Y-alkylguanidine compound.
  • One compound resulting from such fluorinations is as follows:
  • Hete s are generally described by the following formulae:
  • n 0, 1 , 2 or 3
  • L, , N or Q CH 2 , CH, O, N, NH, S, CO, alkyl, ha!oaikyl, aikoxv, haloa!koxy,
  • 18 F is added to an heteroarylalkylguanidine compound.
  • exemplary compounds resulting from such fluorinations are as follows:
  • the radiotracing agents of the present technology find many uses.
  • the radiotracing agents of the present technology find use as imaging agents within nuclear medicine imaging protocols (e.g., PET imaging, SPECT imaging).
  • the radiotracing agents of the present technolog are useful as imaging agents within PET imaging studies.
  • PET is the study and visualization of human physiology by electronic detection of short ⁇ lived positron emitting radiopharmaceuticals. It is a non-invasive technology that quantitatively measures metabolic, biochemical, and functional activity in living tissue.
  • the PET scan is a vital method of measuring body function and guiding disease treatment. It assesses changes in the function, circulation, and metabolism of body organs. Unlike MRI (Magnetic Resonance Imaging) or CT (Computed Tomography) scans that primarily provide images of organ anatomy, PET measures chemical changes that occur before visible signs of disease are present on CT and MRI images.
  • MRI Magnetic Resonance Imaging
  • CT Computerputed Tomography
  • PET visualizes behaviors of trace substances within a subject (e.g., a living body) having a radioimaging agent administered therein by detecting a pair of photons occurring as an electron/positron annihilation pair and moving in directions opposite from each other (see, e.g., U.S. Patent No. 6,674,083, herein incorporated by reference in its entirety).
  • a PET apparatus is equipped with a detecting unit having a number of small-size photon detectors arranged about a measurement space in which the subject is placed.
  • the detecting unit detects frequencies of the generation of photon pairs in the measurement space on the basis of the stored number of coincidence -counting information items, or projection data, and then stores photon pairs occurring as electron/positron annihilation pairs by coincidence counting and reconstructs an image indicative of spatial distributions.
  • the PET apparatus plays an important role in the field of nuclear medicine and the like, whereby biological functions and higher-order functions of brains can be studied by using it. Such PET apparatu ses can be roughly classified into two-dimensional PET apparatuses, three-dimensional PET apparatuses, and slice-septa-retractable type three-dimensional PET apparatuses.
  • a PET detector or camera typically consists of a polygonal or circular ring of radiation detection sensors placed around a patient area (see, e.g., U.S. Patent No. 6,822,240, herein incorporated by reference in its entirety).
  • Radiation detection begins by injecting isotopes with short half-lives into a patient's body placed, within the patient area. The isotopes are absorbed by target areas within the body and emit positrons. In the human body, the positrons annihilate with electrons. As a result thereof, two essentially monoenergetic gamma rays are emitted simultaneously in opposite directions. In most cases the emitted gamma rays leave the body and strike the ring of radiation detectors.
  • the ring of detectors includes typically an inner ring of scintillation crystals and an outer ring of light detectors, e.g., photomultiplier tubes.
  • the scintillation crystals respond to the incidence of gamma rays by emitting a flash of light (photon energy), so-called scintillation light, which is then converted into electronic signals by a corresponding adjacent photomultiplier tube.
  • a computer or similar, records the location of each light flash and then plots the source of radiation within the patient's body by comparing flashes and looking for pairs of flashes that arise simultaneously and. from the same positron-electron annihilation point. The recorded data is subsequently translated into a PET image.
  • a PET monitor displays the concentration of isotopes in various colors indicating level of activity. The resulting PET image then indicates a view of neoplasms or tumors existing in the patient's body.
  • PET detector arrangement is known to have a good energy resolution, but relatively bad spatial and temporal resolutions.
  • Early PET detectors required a single photomultiplier tube to be coupled to each single scintillation crystal, while today, PET detectors allow a single photodeteetor to serve several crystals, see e.g. U.S. Pat, Nos. 4,864,138; 5,451,789; and 5,453,623, each herein incorporated by reference in their entireties). In such manner the spatial resolution is improved or the number of photodetectors needed may be reduced.
  • Single Photon Emission Computed Tomography is a tomographic nuclear imaging technique producing cross-sectional images from gamma ray emitting radiopharmaceuticals (single photon emitters or positron emitters).
  • SPECT data are acquired according to the original concept used in tomographic imaging: multiple views of the body part to be imaged are acquired, by rotating the camera detector head(s) (e.g., of an Anger camera) around a craniocaudal axis.
  • FQV axial field, of view
  • SPECT cameras are either standard gamma cameras that can rotate around the patient's axis or consist of two or even three camera heads to shorten acquisition time.
  • Data acquisition is over at least half a circle (180°) (used by some for heart imaging), but usually over a full circle.
  • Data reconstruction takes into account the fact that the emitted rays are also attenuated within the patient, e.g., photons emanating from deep inside the patient are considerably- attenuated by surrounding tissues. While in CT, absorption is the essence of the imaging process, in SPECT, attenuation degrades the images. Thus, data of the head reconstructed without attenuation correction may show substantial artificial enhancement of the peripheral brain structures relative to the deep ones.
  • the simplest way to deal with this problem is to filter the data before reconstruction.
  • a more elegant but elaborate method used in triple head cameras is to introduce a gamma-ray line source between two camera heads, which are detected by the opposing camera, head after being partly absorbed by the patient. This camera head then yields transmission data while the other two collect emission data. Note that the camera collecting transmission data has to be fitted, with, a converging collimator to admit the appropriate gamma rays.
  • SPECT is routinely used in clinical studies.
  • SPECT is usually performed, with a gamma camera comprising a collimator fixed on a gamma detector that traces a revolution orbit around the patient's body.
  • the gamma rays, emitted by a radioactive tracer accumulated in certain tissues or organs of the patient's body, are sorted by the collimator and. recorded by the gamma detector under various angles around the body. From the acquired planar images, the distribution of the activity inside the patient's body is computed using certain reconstruction algorithms.
  • the radiotracing agents of the present invention are present.
  • radiotracing agents of the present technology are provided to a nuclear ftharmacist or a clinician in kit form.
  • a pharmaceutical composition produced according to the present technology comprises use of one of the aforementioned, radiotracing agents and a carrier such as a. physiological buffered saline solution or a physiologically buffered sodium acetate carrier. It is contemplated that the composition will be systemically administered to the patient as by intravenous injection.
  • Suitable dosages for use as a diagnostic imaging agent are, for example, from about 0.2 to about 2.0 mCi of ⁇ 31 labeled radiotracing agent for the adrenal medulla or tumors therein, and from about 2.0 to about 10.0 mCi of the I- 123 labeled agent for imaging of the heart and adrenal medulla or tumors therein.
  • a higher dosage is required, for example, from about 100 to about 300 mCi of the radiotracing agent material.
  • Wieland, et al Myocardial Imaging with a Radioiodinated Norepinephrine Storage Analog," J. Nucl. Med. 22:22-31, 1981; Valk, et al: "Spectrum of
  • a radiosynthetic scheme was used for preparing [ 18 F]4F-MHPG in which an intermediate fluorine- 18 labeled compound 4-[ 18 F]fluoro-/32eia- tyramine ([ 18 F]4F-MT) was produced using a conventional method for preparing 6-L 18 F]fluoro-dopamine (see, e.g., Ding et al. (1991) "Synthesis of high specific activity 6- [ 18 F]fluorodopamine for PET studies of sympathetic nervous tissue", J Med Chem. 34: 861-3) as modified by Langer (see, e.g., Langer et al.
  • reaction schemes or reaction schemes comprising one or more conventional steps, for producing compounds according to the technology (e.g., a 18 F"labeled phenethylguanidine) were tested, and found to be
  • the methods relate to a two- step reaction to prepare a 18 F-phenethylguanidine (see Figure 2A),
  • the 18 F-labeling step uses a diaryliodonium salt precursor with an N-protected phenethylamine moiety instead of the guanidine group used in the first method.
  • the N-Boc- aminoethylphenyl(2 _ thienyl) iodonium salt provides very high radiochemical yields in the 18 F-labeling step.
  • Treatment with mild acid for simple N-Boc deprotection followed by purification using a C18 Sep-Pak delivers 4-[ 18 F]fTuorrr neia-tyramiiie as an intermediate.
  • an automated method was developed for the preparation of [ 18 F]4F-MHPG (see, e.g.. Figure 2B ) .
  • a single ls F-labeling step is followed by additional steps to yield the final product.
  • two reaction modules e.g., GE TRACERlab FXFN modules
  • GE TRACERlab FXFN modules in adjacent hot-cells
  • the first FXFN module was used for production of 3-benzyloxy-4-[ 18 F]fluoro- 22ei-3-tyramine [ 18 F] ( Figure 2B, compound 4), while the second FXFN module was used to convert the [ 18 F] compound 4 ( Figure 2B) into the final product 1, as shown in Figure 2B.
  • the iodoniu salt precursor Figure 2B, compound 2
  • Cs[ 18 F]F in DMF containing the radical scavenger TEMPO to prepare the [ 1S F] compound 3 ( Figure 2B).
  • Removal of the Boc protecting group from 3 using 1.0 N HC1 provided the intermediate L 18 F] compound 4.
  • the technology comprises
  • 18 F-laheled arylalkylguanidines including, but not limited to, 18 F- benzylguanidines and 18 F ⁇ arylpropylguani dines, such as 4-[ 18 F]fluoro ⁇ meta-hydroxy-benzylguanidine and 4- [ 18 F]fluoro-meta-hydroxy ⁇ phenpropyl guani di ne .
  • Embodiments to prepare 18 F-labeled benzylguanidines are distinct from conventional approaches for preparing compounds such as meta- 8 F]fluoro-benzylguanidine (see, e.g., Garg, et al. (1994) "Synthesis and preliminary evaluation of para- and meta-[ 18 F]fluorobenzylguanidine", Nucl Med Biol 2,1' ⁇ 97-103). It is contemplated that novel imaging agents comprising [ 18 F] -labeled arylpropylguanidines are useful PET imaging agents of cardiac sympathetic innervation and adrenergic tumors.
  • the labeling technology is not limited to particular 18 F-labeled
  • arylalkylguani dines , aryl - Y- alkylguani dine s , and/or heteroarylalkylguani dine s .
  • the technology relates to embodiments of arylalkylguanidine compounds having a general structure ⁇ r Alkoxy
  • n 0, 1 , 2 or 3
  • L, M, N or Q CH 2 , CH, O, N, NH, S, CO, alkyl, haloalkyl, alkoxy, haloalkoxy,
  • arylalkylguaxn dines aryl-Y-alkylguanidines
  • heteroarylalkylguanidines e.g., for use as imaging agents, e.g., in PET imaging.
  • some embodiments provide methods in which an 18 F ⁇ laheled arylalkylguanidine is produced from an iodonium salt precursor by a single step reaction in solution, e.g., lodonium Salt
  • the technology provides related embodiments in which an arylalkylguanidine produced from an iodonium salt precursor in a single step using a linker, e.g.,
  • Step 2 coupling with guanidinating reagent
  • some embodiments provide methods in which an 1S F- labeled aryl-Y-alkylguanidine is produced from an iodonium salt precursor by a single step reaction in solution, e.g., lodonium Salt
  • the technology provides related embodiments in which an aryl ⁇ Y -alky Iguani dine is produced from an iodonium salt precursor in a single step using a linker, e.g.,
  • Step 2 coupling with guanidinating reagent
  • some embodiments provide methods in w 7 hich an 18 F-labeled heteroarylalkylguani dine is produced from an iodonium salt precursor by a single step reaction in solution, e.g.,
  • heteroarylalkylguanidine is produced from an iodonium salt precursor in a single step using a linker, e.g.,
  • Example 2 demonstrates that compositions comprising 18 F-labeled aryl-Y- alkylguanidine compounds are successful as PET imaging agents. These results are based, on evaluating n C-labeled analogs of phenoxyethylguan dine as potential imaging agents for cardiac sympathetic innervation and adrenergic tumors in an isolated rat heart system.
  • Heterocyclic compounds with side chains terminating with a guanidine group are good substrates of the norepinephrine transporter (NET) and have pharmacological activity in cardiac sympathetic innervation. See, e.g., Broadley KJ. AuUmomic Pharmacology. London.: Taylor & Francis (1996).
  • NET norepinephrine transporter
  • the heteroarylalkylguanidine compound 2-(2,3-dihydro-l,4-beiizodioxin-2- yimethyl) guanidine which is known as "guanoxan” has pharmacological activity, in particular, guanoxan exhibits "sympatholytic" activity that prevents the release of norepinephrine from nerve terminals.
  • Example 3 shows that a guanoxan compound is useful as an. imaging agent.
  • ring- hydroxylated analogs of guanoxan showed favorable uptake and retention time.
  • an i8 F-labeled analog of a ring hydroxylated analog of guanoxan. e.g., 6- [ 18 F]fluoro-7-hydroxy-guanoxan
  • an imaging agent for example to image adrenergic tumors and cardiac sympathetic innervation.
  • imaging agents with structural similarity to phenethylguamdmes ⁇ e.g., arylalkylguani dines, aryl-Y- alkylguanidines, and heteroarylalkylguanidines) were evaluated and the results demonstrate that these additional agents share a unified clinical application with 18 F-labeled phenethylguanidines as imaging agents.
  • the specific imaging targets of these imaging agents include, but are not limited to, the sympathetic innervation of the heart and other organs, the adrenal medulla, and
  • neuroendocrine tumors such as neuroblastoma and pheochromocytoma.
  • Plasma was processed for injection onto a reverse-phase HPLC system equipped with a radiation detector. The percentages of intact parent tracer and. radiolabeled metabolites were determined as a function of time.
  • [ 18 F]4-MHPG has a retention time R of approximately 11.2 minutes while the main polar radiometabolite formed has an J3 ⁇ 4 of approximately 7.9 minutes.
  • the main radiometabolite formed is more polar than the parent compound, [ 18 F]4-MHPG.
  • the metabolite has been identified as the sulfur conjugate of [ !8 Fj4-MHPG based on in vitro incubations of the parent compound with a monkey liver cytosol fraction and the required cofactor S'-phosphcr adenosine-5'phosphosulfate (PAPS). After only 1 minute of in vitro incubation, approximately 70% of [ 18 F]4-MHPG was sulfur conjugated, and after 20 minutes of incubation, 100% was in the sulfur-conjugated form (Figure 4B). Sulfur conjugation occurs at the meta-bydroxyl group ( Figure 4C).
  • tracers are metabolized more quickly in monkeys than in humans, e.g., tracer metabolism rates are typically 2 to 3 times slower in humans than in monkeys.
  • a longer lifetime in human subjects is advantageous, e.g., to allow cardiac neurons to accumulate the tracer for a longer period of time, thus providing more kinetic data for quantitative analyses.
  • a metabolism rate that is 2 to 3 times slower in humans allows an imaging study of approximately 30 minutes to provide all the kinetic data needed for quantifying cardiac nerve density.
  • metabolic breakdown essentially
  • [ 18 F]4- MHPG may have some activity as a depletor of norepinephrine from storage vesicles in sympathetic neurons, it may prove beneficial to have it completely metabolized to the sulfur conjugate within 1 hour after injection into a human subject.
  • Patlak graphical analysis was used, which uses a mathematical transformation of the kinetic data C p (i) and Ct ) to generate a 'Patlak plot' having a characteristic linear phase (see, e.g., Patlak and Blasberg (1985) "Graphical evaluation of blood-to-brain transfer constants from multiple- time uptake data. Generalizations.” J Cereb Blood Flow 5 " ⁇ 584-90), The slope of the linear portion of a Patlak plot, K P (ml/min/g), provides an alternate estimate of the 'net uptake rate constant' K (ml/min/g). Thus, for the model structure used ( Figure 7), the slope of the Patlak plot is given by K P ⁇ (j3 ⁇ 4J3 ⁇ 4) / (ia + is).
  • Patlak graphical analysis of one of the control studies in a rhesus macaque monkey is shown in Figure 10.
  • ICso half-maximal inhibitory concentration
  • OLINDA/EXM are shown in Table 4. Organs with the highest absorbed dose estimates included the urinary bladder wall (0,666 rad/mCi), upper lower intestine (0.221 rad/mCi), small intestine (0.201 rad mCi), and the heart wall (0.201 rad mCi). An 'effective dose' of 0.091 rem/mCi was estimated for [ 18 F]4F- MHPG. Under United States Federal Regulations governing research with a new radiopharmaceutical (21 CFR ⁇ 361.1), the maximum allowable radiation absorbed dose to an individual organ (other than the gonads) is 5 rad.
  • Y is (), S, or NH) for use as PET tracers.
  • n 04F- MHPEG and its positional isomer, n C-3-fluoro-para-hydroxy- phenoxyethylguanidine (11C-3F-PHPEG), were synthesized. Isolated rat heart studies with these two agents demonstrated rapid uptake rates with very long retention times ( Figure 13). "04F-MHPEG had a neuronal uptake rate of 2.66 mL/min/g wet and was effectively trapped inside storage vesicles. n C-3F-PHPEG had a faster uptake rate of 4.26 mL/min/g wet and. cleared with a major half time of 16.9 hour.
  • these compounds are contemplated, to find use as PET imaging agents, e.g., for localizing adrenergic tumors.
  • n Oguanoxan ( n C ⁇ GQX) was synthesized and experiments were conducted to evaluate its kinetics in the isolated rat heart (Table 6).
  • data were acquired in studies of the kinetics of two ring-hydroxylated analogs of guanoxan ⁇ n C-7 _ hydroxy-guanoxan ( O7H-G0X) and n C-6-hydroxyguanoxan ( 11 C"6H-GOX) ( Figure 14).
  • the 7-hydroxy analog demonstrated a more rapid uptake and a longer retention time.

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Abstract

La présente invention concerne une technologie associée à des agents d'imagerie et en particulier, mais non exclusivement, des procédés de fabrication de phénéthylguanidines marquées par le fluor-18 et leurs utilisations.
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